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The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects
Author(s) -
Neumann Ulf,
Machauer Rainer,
Shimshek Derya R.
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14582
Subject(s) - amyloid precursor protein secretase , amyloid precursor protein , genetically modified mouse , neuroinflammation , neurodegeneration , pharmacology , chemistry , gamma secretase , alzheimer's disease , amyloid (mycology) , neuroscience , biochemistry , disease , transgene , medicine , biology , pathology , inorganic chemistry , gene
Inhibition of β-secretase 1 (BACE-1; also known as β-site amyloid precursor protein-cleaving enzyme-1) is a current approach to fight the amyloid-β (Aβ) deposition in the brains of patients with Alzheimer's disease, and a number of BACE-1 inhibitors are being tested in clinical trials. The BACE-1 inhibitor NB-360, although not a clinical compound, turned out to be a valuable pharmacological tool to investigate the effects of BACE-1 inhibition on the deposition of different Aβ species in amyloid precursor protein (APP) transgenic mice. Furthermore, chronic animal studies with NB-360 revealed relationships between BACE-1 inhibition, Aβ deposition, and Aβ-related downstream effects on neuroinflammation, neuronal function, and markers of neurodegeneration. NB-360 effects on the processing of physiological BACE-1 substrates as well as on nonenzymatic BACE-1 functions have been investigated, complementing studies in BACE-1 knockout mice. Because NB-360 is also an inhibitor for BACE-2, nonclinical studies in adult animals revealed physiological effects of BACE-2 inhibition. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.